A Comprehensive Report on Acasunlimab (GEN1046/BNT311): A Novel Bispecific Antibody for CPI-Refractory Malignancies

Executive Summary

Acasunlimab, also identified by the development codes GEN1046 and BNT311, is an investigational, first-in-class bispecific antibody at the forefront of next-generation immuno-oncology therapeutics.[1] Engineered using Genmab's proprietary DuoBody® technology platform, this molecule is designed as an Fc-inert bispecific antibody that concurrently targets two critical immune regulatory pathways: Programmed Death-Ligand 1 (PD-L1) and 4-1BB (CD137).[2] Its innovative mechanism of action is twofold, combining the established principle of immune checkpoint inhibition with a novel, safety-engineered approach to T-cell co-stimulation. Acasunlimab simultaneously blocks the inhibitory PD-1/PD-L1 axis while delivering a conditional, PD-L1-dependent agonistic signal to the 4-1BB receptor on T cells and Natural Killer (NK) cells, a design intended to localize potent immune activation within the tumor microenvironment and mitigate systemic toxicities.[5]

The clinical development program has primarily focused on addressing the significant unmet medical need in patients with malignancies that have progressed on or after standard-of-care checkpoint inhibitor (CPI) therapy. The most compelling clinical data to date emerge from the randomized, Phase 2 trial (NCT05117242) in patients with previously treated, PD-L1-positive metastatic non-small cell lung cancer (mNSCLC). In this challenging patient population, the combination of acasunlimab with the anti-PD-1 antibody pembrolizumab, administered on a once-every-six-weeks (Q6W) schedule, demonstrated a remarkable median Overall Survival (mOS) of 17.5 months and a 12-month OS rate of 69%.[8] These results stand in stark contrast to the historically poor outcomes with standard chemotherapy in this setting.